DE1620369A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

SANDOZ AG ■ ■; '■ "Oase 6QO" 6Q53 Basel patent attorneys

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. PspL-Ing. G, Öannenberg -; - \. , - .- ;. "" ":. *" i

..- .. · -. Dr .. V. Schmied-Kowereik.-; _; ■ ". ■; ■■ Dr. P. Wemhoy, Dr. Ö. Gucfei

Process soar manufacture rigaey »heterocyclic ^; -

Di © ^ ©! »Lying © SyfiM« ag bsS? Iff ^ ^: f $ s? Fate @ a suy Psrstellwig voa compounds äer alig ^ msiaap fo ^ m ^ l j, wefia B Sp * @iae ÄÄylgruppe with 1-4 carbon toroes stands, uad

Erfinduagsgemass can .- importance yeast UHD A Ä ^ Wassfffstoff mm su Yerbindtogea dsr * allgemelöea formula I and their S ^ räadditionssalzett gelsajgeß by _a mas Teröindwigea the general 'R NEN above formula IX imvln,' or '. lower alkyl _β stands on azt look. ©-known manner Olise "cyclization% mt <^ ft st'Wi _e wad dl © s" ertelteas

I possibly sssefeliesseadl aisf aa siefe "feekgaate ¥ © is © in their

Ringsefeliass- v © ss fe ^ biffidöagea d @ r general «formula II, in which R has the above meaning feat iaad, A tü.T MgÄ @ g> ®s Al & yl, Vk & zm in the presence of Natriuin-ß-raethoj ^ -Ethaß © ! durefe- iCoetei in 0-Methoxf "-ithaaoI during 1 to 5 hours m Hie & river 'or & HEV Average The cooking can be carried out in. of glacial acetic acid. Another method is *; that the compounds a of the general formula II, in which A stands for lower llsyl, are hydrolyzed in a manner known per se to compounds of the general formula II in which A stands for hydrogen, and these are heated to 140 ° -16O ° for 1 to 2 hours . The compounds of the general formula I thus obtained are then in a manner known per se, for example, by crystallization from a suitable

0 0 9 8 1 A / 1 8 7 2 BAD 'qfüqiual S.

Documents (Art, 7 § ΐ Abs, 2 No. 1 Ssfö 3 dee Anderunosgee. V. 4.9.1967)

- a - 600-6055

organic solvent, isolated, purified by recrystallization and optionally then in a manner known per se into their acid addition salts convicted. ·

The starting compounds of the general formula II are new and as well as the method for their production described below part of the present invention *

^ To compounds "of the general formula II can be obtained by

ß-2-ThienylEthylamin iß an inert under the reaction conditions organic solvents, for example tetrahydrofuran, dioxane, dimethylforraaside or Diiaethylsulfoxyd * at room temperature with compounds of the general Formula III, in which R has the above meaning, is reacted, the reaction mixture being continued for 30 minutes on to complete the reaction Heated water bath. The compounds of the general formula obtained in this way IV, where R has the above meaning., Are then added by adding water precipitated from the reaction mixture, their amino group by introducing a Tosyl, benzenesulfonyl, mesyl or similar protective group on known per se Way protected (for example, the tosyl radical can be reacted with p-Toluenesulfonic acid chloride under Schotten-Baumann conditions or in Pyridln), and the compounds thus protected of the general Formula IV by boiling e.g. in xylene in the presence of phosphorus pentoxide, in Phosphorus oxychloride or in polyphosphoric acid a ring closure according to Bischler-Napieralski subject. The protective groups are then split off in a manner known per se (for example with the aid of concentrated sulfuric acid, or by

0098U / 1872

3 ■■ '-; 600-6053

# 20369.

Dissolve the tosylates in phenol and glacial acetic acid and heat this solution in the presence of hydrogen bromide to 50-60 ⁰ ) »and the compounds of the general formula V, in which R has the above meaning, in a manner known per se, for example by Heating in ethanolic solution in the presence of sodium borohydride »to compounds of the general formula VI, in which R has the above meaning, and these are reduced with a lower alkyl chloro or bromoacetate in the presence of an acid-binding agent, for example triethylamine, in a suitable organic substance which is inert under the reaction conditions Solvent, such as ethanol, implemented.

The compounds of general formula I prepared by the process according to the invention have an asymmetric carbon atom and can therefore be obtained both as racemates and in optically active form. The racemates obtained by the process according to the invention can be converted into their optically active _{v according to methods known per se} Individual components are split up. Optically active compounds of the general formula I can, however, also be obtained by separating them from their optically active starting materials, respectively, by the above process. |

Establishes interconnections.

The optically active compounds of the general formula obtained in this way I can then, if necessary, in a manner known per se be converted into their acid addition salts.

The compounds of the general formula prepared according to the invention I are crystalline substances at room temperature that help can be converted into their acid addition salts by suitable organic or inorganic acids. As inorganic

00981 V / 1872 - -

- ■ 4 - 600-6055

For salt formation, acids are hydrochloric acid, hydrobromic acid, Sulfuric acid or phosphoric acid, and as organic acids tartaric acid, methanesulfonic acid, succinic acid, Zi " tronic acid, acetic acid, maleic acid, fumaric acid or benzenesulfonic acid are suitable.

The compounds of the general formula prepared according to the invention I and their salts with pharmaceutically acceptable organic acids are valuable pharmaceuticals. They stand out in particular by acting on the central nervous system. This manifests itself in a calming as well as an antispasmodic Effect in amphetamine antagonism and in potentiation of the anesthesia caused by barbiturates. Also work the compounds are anti-inflammatory. The 12-chloro-9-methyl-

diazepin-8-one has a calming effect on the central nervous system and It also has an anticonvulsant and anti-inflammatory effect. The compound also has a calming effect on septalized rats, amphetamine antagonism and can potentiate the effect caused by barbiturates »The daily The dose of compounds of the general formula I to be administered orally or parenterally is 10 to 200 mg.

0 0 98 H / 1 87 2

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sin oaer in

The new compounds can be used as medicinal products by all] speaking medical forms used for oral or parenteral © administration ■. will. For the purpose of producing suitable dosage forms, these are mixed with inorganic or organic, pharmacologically indifferent auxiliaries. The auxiliary materials used are e.g.

for tablets and dragees s milk sugar starch »talc, stearic acid, etc. for syrups t cane sugar, invert sugar, glueose solutions, etc.

for injection preparations: water, alcohols, glycerine, vegetable oils

and the like

In addition, the preparations can contain suitable preservation, stabilization, ([ Contain wetting agents, solubilizers, sweeteners, colorings, aromas, etc.

Each of the above-mentioned pharmacologically active compounds can be brought into the form of a tablet with the following composition, for example for oral administration:
1-3 % binder. (". B" Xra ^ oanth} "3 ° 10 <£ - atSrke". 2-10 ^ talc, 0.25-1 % magnesium stearate, corresponding amount of active substance and

ad 100 % filling substance, e.g. lactose.

In the following examples, which show the execution of the method | rens, but are not intended to limit the invention in any way, all temperatures are given in degrees Celsius.

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600-6055

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^ P. NO

O i-C ^ -C-O-A

-NHR

Cl-

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Q-C

Cl-

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Cl-

-NHR

009814/1872

600-6053

-NHR

Cl-

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Example 1: 12-chloro-9-niethyl-4,5,1 > 8,9 ₁ l ^ b -hexahydro-thieno - [5 »2> elpyrido [l / 2-d1benzo [l _> 41d iazepin ~ 8-one .

a) N- (β-2-Kiienyrathyl) -2-methylainino-5-chlorobenzamide.

2.7 g of ß-2-thienyrethylamine are dissolved in 9 cc of dioxane, and the solution is then mixed with 4.5 g of ö-chloro-N-methyl-isatoic anhydride, the reaction starts immediately. After its completion, the The mixture was heated on the steam bath for another 50 minutes. Then it is cooled down, and 20 cc of water are added, the N- (ß-2-thienylethyl) -2-methylamino-5-chlorobenzamide precipitates from m.p. 138-140 °.

^ b) N- (ß-2-thienylethyl) -S-chloro ^ -methyltosylamino-benzamide.

To a solution of 5.5 g of N- (ß-2-thienylethyl) -2-methylamino-5-chlorobenzaride 5 * 5 g of p-toluenesulphonic acid chloride are in 25 cc of pyridine added, and the mixture thus obtained is then heated for 90 minutes. The resulting clear brown solution is cooled and then mixed with 5 cc of water. This is followed by 50 minutes * at room temperature held. After evaporation of the solvent in vacuo, the residue is extracted with ethyl acetate and water in a separating funnel. To Separation of the phases, the organic phase obtained is extracted twice with dilute aqueous sodium bicarbonate solution, then over Dried sodium sulfate and freed from solvent in vacuo. The one with it The oily residue obtained is recrystallized from diethyl ether. That N- (ß-2-thienylethyl) -5-chloro-2-methyltosylamino-benzamide melts at 109 °.

c) 4- (5-chloro-2-methyltosylaminophenyl) -6,7-dihydro-thieno (5,2-c] pyridine. 6g of N- (ß-2-thienyrethyl) -5-chloro-2-raethyltosylamino-benzamide are heated in 40 cc phosphorus oxychloride for 90 min. On the reflux condenser. After evaporation of the phosphorus oxychloride in vacuo, the residue is in Dissolved methylene chloride, and the solution twice with 1 N aqueous sodium hydroxide solution. extracted. AnsohliessepxJ- the methylene chloride solution is over

0 098 14/187 2> - »

B original.

ν-, 9 ^; V. 600-6055

Sodium sulfate · dried and evaporated to dryness in vacuo, the 4- (5-chloro-2-methyltosylamino * phen ^ as

oily residue remains, f g 2 ö 369

^ ibi ^ chloro- ^ methylamino- ^

0.5 g ^ -CS-chlorine ^ methyltösylamino-phen ^^

[5, »2-c] pyridine are dissolved in j cc concentrated sulfuric acid * and the resulting Solution left to stand for 2 hours at room temperature. Then will the solution ice and conc. aqueous sodium hydroxide solution added so long until the device reacts alkaline. Then twice with methylene chloride extracted, the methylene chloride solution washed with water »over sodium sulfate dried and evaporated to dryness in vacuo. Per residue will dissolved in ethyl acetate, and the insoluble matter was filtered off from the solution. That The filtrate is evaporated, the 4- (5-CMor-2-methylamino-phenyl) -6,7-dihydro-thienof3,2-c] pyridine remains as an amorphous residue.

e) 4- (5-chloro-22methylami ^

5 g are added to a solution of 2.5 B, 4- (5-chloro-2-methylarainophenyl) -6,7-dihydro-thieno £ 3.2-c pyridine in 100 ce 90 percent ethanol Sodium borohydride and the mixture thus obtained is refluxed for 2 1/2 hours. It is then cooled and the excess sodium borohydride is destroyed by adding acetic acid. After acidifying the mixture with hydrochloric acid, the ethanol is removed in vacuo, the solution is then made alkaline with dilute aqueous sodium hydroxide solution and extracted three times with methylene chloride. The organic phases are combined, dried over sodium sulfate and freed from the solvent in vacuo. The remaining residue as 4 * (5-CMOR-2-methylamino-phen ^ l5-4,5,6,7-tetra- hydro-· thienot3,2-c] pyridin _t melts after Urokristallisiereii a 's ethanol at 90 91 ° / 111-112 ° (double point of angle).

■ '■■ - ■'. ■ ■; ■ '.' ■ ■ '■■■■ "■ V. ■

0098 14/1872

A mixture consisting of 13.9 g of 4- (5-chloro-2-methylaminophenyl) -4,5,6,7-tetrahydro-thienot3,2-c] pyridine, 10.6 g of triethylamine, 16.7 S Ethyl bromoacetate and 200 cc absolute ethanol, is refluxed for 17 hours

-Λ

cooked cooler. Then the solvent is evaporated, and the The residue dissolved in benzene. To remove the unreacted starting material, the benzene solution is extracted twice with 0.5 N hydrochloric acid and then washed with water and an aqueous sodium bicarbonate solution. ^ After drying over sodium sulfate, the benzene solution is evaporated in vacuo, the 4- (5-chloro-2-methylaminophenyl) -5-carbethoxymethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine remains as a pale yellow oil.

g) ^ -Chlor ^ -methyl- ^, 5.7 * 8,9,13b-hexahydro-

tMeno [3,2-c] pyridori, 2-d] benzo [1, jjldiazepin-S-one.

16 g of 4- (5-chloro-2-methylamino-phenyl) -5-carbethoxymethyl-4,5,6J7-tetrahydro-thieno [3 »2-c] pyridine are dissolved in 175 ^{cc of} glacial acetic acid, and the resulting solution for 2 Heated for 1/2 hour on a reflux condenser in such a way that half of the solvent is distilled off at the same time. Then P the reaction mixture is evaporated in vacuo, and the residue in Dissolved ethyl acetate. The solution is extracted three times with dilute hydrochloric acid. The aqueous-hydrochloric acid phases are combined, made alkaline with aqueous sodium hydroxide solution and then extracted three times with methylene chloride. The methylene chloride extracts are combined, dried over sodium sulfate and evaporated in vacuo. In treating the residue with ethanol, the 12-chloro-9-methyl-4,5 _# 7 "8.9 crystallized" 13bhexahydro-thieno [3 2-c _J] pyrldo [l, 2-d] benzo [l _# 4idiazepln- 8-one of m.p. 150-152 °.

QÜ98U / 1872

Example 2: Description of a tablet set-up s

600-6053 Ί & Ζ0369

-o! i . . »* ■ .. βθ g

Cornstarch powder. ·. ·> .... . . . . ,. . . ... .. 5 p

Magnesium stearate. . . . . . . . «..» .. «« ..... . 0.5 g

Alcohol SD-30)

) in the necessary quantities
Best. Water)

The weight of the tablets produced depends on the to be administered dose of active ingredient.

0 098IAM 87 2

Claims (4)

- 12 - 600-6053 claims; 1. Compounds of the formula 'I, wherein R represents an alkyl group with 1-4 carbon atoms, and their acid addition salts. 2. 12-Chloro-9-methyl-4,5,7,8,9,13b-hexahydrothieno [3,2-c] pyrido [1,2-d] benzo [1,4] diazepin-8-one . 5. Process for the preparation of compounds of the formula I ,. ^ where R is an alkyl group with 1-4 carbon atoms, and their acid addition salts, characterized in that compounds of the formula II in which R has the above meaning and A is hydrogen or lower alkyl, an intramolecular one Subject to ring closure and the compounds obtained in this way, optionally converted into their acid addition salts. 4. The method according to claim 3, characterized in that the ring closure of compounds of the formula II, in which A stands for * lower alkyl, by boiling in the presence of sodium β-methoxy-ethanol in ß-methoxy-ethanol or by boiling in Glacial acetic acid is carried out. 5 · The method according to claim 3 * characterized in that the Ring closure of compounds of the formula II in which A is hydrogen by heating to a temperature of 14o-160 ° C is carried out for 1 to 2 hours. 3700 / SP / lL ./'V SANDOZ AG 0098 U / 1872 / '3 New documents _(Art . _{7 §} , _Ab , _{2 N} ,, ^ , '>"/ ^ ^{ t £ 3_de_e Aodetuausge «. v. 4.9.196? BATH ORIGINAL